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Research In Viral Eradication of HIV Reservoirs (RIVER)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by Imperial College London
Sponsor:
Collaborators:
Medical Research Council
University of Oxford
University of Cambridge
Chelsea and Westminster NHS Foundation Trust
Royal Free Hospital NHS Foundation Trust
Brighton and Sussex University Hospitals NHS Trust
Guy's and St Thomas' NHS Foundation Trust
Central and North West London NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT02336074
First received: October 23, 2014
Last updated: October 10, 2016
Last verified: October 2016
  Purpose

This study will be a two-arm prospective 1:1 randomised controlled trial comparing:

Arm A: 4-drug cART including raltegravir (combination ART cART - control) Arm B: 4-drug cART including raltegravir (cART) plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total).

We hypothesise that this intervention in primary HIV infection will confer a significant reduction in the latent HIV reservoir when compared with cART alone.


Condition Intervention Phase
HIV
Drug: Combination Antiretroviral Therapy (cART)
Drug: Raltegravir
Drug: Vorinostat
Biological: ChAdV63.HIVconsv (ChAd)
Biological: MVA.HIVconsv (MVA)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Research In Viral Eradication of HIV Reservoirs

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Total HIV DNA from CD4 T-cells [ Time Frame: Averaged across post-randomisation week 16 and 18 ]
    The average of two measures taken at post-randomisation week 16 and 18


Secondary Outcome Measures:
  • Clinical and laboratory adverse events [ Time Frame: 42 weeks ]
  • Further assessment of the HIV reservoir [ Time Frame: 42 weeks ]
    Further assessment of the HIV reservoir e.g. HIV integrated DNA; HIV cell associated RNA; plasma HIV RNA measured with an ultra-low copy assay i.e. with a threshold of <1 copy/ml and viral outgrowth assays.

  • Studies of immune function [ Time Frame: 42 weeks ]
    Studies of immune function including measuring the latently-infected resting memory T-cells and cytotoxic immune responses

  • Changes in plasma IL-6 (an inflammatory biomarker) [ Time Frame: 42 weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of IL-6, an inflammatory biomarker

  • Changes in plasma hCRP (an inflammatory biomarker) [ Time Frame: 42 Weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of hCRP, an inflammatory biomarker

  • Changes in plasma TNF-alpha (an inflammatory biomarker) [ Time Frame: 42 Weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of TNF-alpha, an inflammatory biomarker


Estimated Enrollment: 52
Study Start Date: November 2015
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A
Combination Antiretroviral Therapy (cART) including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total)
Drug: Combination Antiretroviral Therapy (cART)
Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.
Drug: Raltegravir
All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.
Other Name: Isentress
Experimental: Arm B
Combination Antiretroviral Therapy (cART) including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Drug: Combination Antiretroviral Therapy (cART)
Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.
Drug: Raltegravir
All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.
Other Name: Isentress
Drug: Vorinostat

Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDAC3 (Class I) and HDAC6 (Class II).

Vorinostat is supplied as capsules containing 100mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate.

Biological: ChAdV63.HIVconsv (ChAd)
Dosage: 5x1010vp .This dose is obtained by injecting 0.37ml of the vaccine at 1.35x1011vp/ml without dilution. This prime vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 00.
Biological: MVA.HIVconsv (MVA)
Dosage: 2x108pfu Administration: This dose is obtained by injecting 0.23 ml of the vaccine IM at 8.6x108pfu/ml without dilution. This boost vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 08 Day 1 (2 prior to start of vorinostat)

Detailed Description:

The study design is a two-arm, open label randomised study. Eligible participants will be treatment-naïve HIV-1 infected adults with primary infection. All participants receive 4-drug combination ART (cART) for the duration of the intervention phase of the study (42 weeks). In patients meeting the criteria for randomisation (eligibility assessed at week 22), participants will either continue cART or receive an intervention consisting of two anti-HIV vaccines separated by 8 weeks followed by 10 doses of the HDACi, vorinostat, in addition to cART. We hypothesise that the prime-boost vaccination will result in the generation of vaccine induced HIV specific CTLs that will recognise HDACi-activated cells of the HIV reservoir and destroy them. The net effect will be a greater reduction in the HIV reservoir defined as HIV total DNA in CD4+ T-cells in the cART+vaccine+HDACi compared to the cART alone. Our strategy is entirely different from previous therapeutic vaccination approaches which have been largely unsuccessful. Immunological priming to conserved HIV proteins will drive CD8+ T-lymphocyte recognition of latently-infected cells rendered immunogenic by HDACi. We anticipate that the viral antigens expressed by latently-infected cells will be unable to adapt to, or escape from, the immune response as they will be expressed directly from chromosomal DNA, avoiding the steps of the viral life-cycle that facilitate immune-driven adaptation. We have chosen a prime-boost immunisation strategy with recombinant replication-defective chimpanzee adenovirus and modified vaccinia Ankara vectors, bearing conserved HIV antigens; these products have been shown to induce high titres of HIV-specific CD8+ T-cells. In addition, these vaccines will drive immune responses against conserved regions of the virus that may be well preserved in individuals with PHI.

Primary HIV Infection (PHI) is a unique period when HIV proviral reservoir is smaller than in chronic disease, is likely to be more homogeneous than in later stage disease and hence is more susceptible to immunological elimination. This provides an opportunity to use a vaccine to re-direct HIV-specific immune responses towards genetically fragile regions in the viral proteome. Immunisation in PHI should result in potent immune responses because ART initiated in PHI preserves CD4 function42 and early ART-mediated viral suppression limits viral diversification, reducing the chance of immune escape. The other key reason for conducting this trial in PHI is that, in some patients, an early sustained course of ART started very early in infection may induce a state of viral remission in which therapy can be stopped without any rebound viraemia. This has been most notably reported in the VISCONTI cohort44 in which 'post-treatment control' was identified in 15.6% of selected individuals.

We hypothesise that the combination of HDACi with immunisation in cART-suppressed PHI will significantly impact the HIV reservoir.

  1. All patients enrolled will receive combination antiretroviral therapy designed to reduce the plasma viral load as quickly as possible, hence the inclusion of the integrase inhibitor, raltegravir. Treating in PHI may restrict the size of the reservoir.
  2. The prime-boost vaccination is designed to enhance the killing capacity of the cytotoxic T cells. This must be given before the HDACi in order to prime and boost a maximal HIV-specific T-cell response to recognise activated viral antigen expression on reservoir cells.
  3. The HDACi is designed to activate the reservoir, and in the presence of the enhanced killing capacity of the CD8+ T cells, results in killing of the cells previously harbouring latent virus, leading to further reductions in the reservoir.

This combined approach has never been used, we hypothesise there will be a 50% reduction in the proviral DNA (the 'reservoir'), in this 'proof-of-concept' study, in those randomised to the vaccine-HDACi intervention compared to those receiving antiretroviral therapy alone.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  1. Aged ≥18 to ≤60 years old
  2. Able to give informed written consent including consent to long-term follow-up
  3. Should be enrolled within a maximum of 4 weeks of a diagnosis of primary HIV-1 infection confirmed by one of the following criteria:

    1. Positive HIV-1 serology within a maximum of 12 weeks of a documented negative HIV-1 serology test result (can include point of care test (POCT) using blood for both tests)
    2. A positive p24 antigen result and a negative HIV antibody test
    3. Negative antibody test with either detectable HIV RNA or proviral DNA
    4. PHE RITA test algorithm (a) reported as "Incident" confirming the HIV-1 antibody avidity is consistent with recent infection (within the preceding 16 weeks).
    5. Weakly reactive or equivocal 4th generation HIV antibody antigen test
    6. Equivocal or reactive antibody test with <4 bands on western blot
  4. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females)
  5. Weight ≥50kg
  6. Willing to be treated with cART including raltegravir and be randomised to continue cART alone or cART plus intervention (HIV vaccines plus HDACi)
  7. Willing and able to comply with visit schedule and provide blood sampling

ENROLMENT EXCLUSION CRITERIA

  1. Women of child bearing potential (WCBP) (b)
  2. In women with intact ovaries and no uterus, any planned egg donation anytime in the future to a surrogate
  3. Intention to donate sperm or father a child within 6 months of the intervention
  4. Co-infection with hepatitis B (surface antigen positive or detectable HBV DNA levels in blood) or hepatitis C (HCV RNA positive)
  5. Any current or past history of malignancy
  6. Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur during the trial e.g.past history of ischaemic or other significant heart disease, malabsorption syndromes, autoimmune disease
  7. Any contraindication to receipt of BHIVA recommended combination antiretrovirals
  8. Any contraindication to receipt of the strand-transfer integrase inhibitor (INSTI), raltegravir
  9. HIV-2 infection
  10. Known HTLV-1 co-infection
  11. Prior immunisation with any experimental HIV Immunogens (including any component of the vaccines used in the RIVER protocol; simian or human adenoviral vaccine; other experimental HIV vaccines)
  12. Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are allowed)
  13. Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis)
  14. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices
  15. Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; any other drugs that prolong QTc; warfarin, aspirin, sodium valproate
  16. Prior intolerance of any of either the components of the vaccine or HDACi,
  17. Uncontrolled diabetes mellitus defined as an HBA1C>7%
  18. Any congenital or acquired prolongation of the QTc interval, with normal defined as ≤0.44s (≤440ms)
  19. Participation in any other clinical trial of an experimental agent or any non-interventional study where additional blood draws are required; participation in an observational study is permitted
  20. Allergy to egg
  21. History of anaphylaxis or severe adverse reaction to vaccines
  22. Planned receipt of vaccines within 2 weeks of the first trial vaccination administered at PR week 00 (including vaccines such as yellow fever; hepatitis B, influenza)
  23. Abnormal blood test results at screening including:

    1. Moderate to severe hepatic impairment as defined by Child-Pugh classification
    2. ALT >5xULN
    3. Platelets <150x109/L
    4. eGFR <90 (c)
    5. uPCR >30 mg/mmol
  24. Physical and laboratory test findings: Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination and/or vital signs that the investigator believes is a preclusion from enrolment into the study
  25. Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate adherence with study requirements
  26. Insufficient venous access that will allow scheduled blood draws as per protocol

    1. using current cut-offs for optical density as defined by PHE
    2. females aged <20 years of age, and weighing <65kg and <168cm in height will need to have an estimation of blood volume (EBV) prior to enrolment, >3500mL before to participate. This circumstance is unlikely to arise as most women between the ages of 18 to 20 years would be of child-bearing potential (CBP) and excluded on that basis.
    3. eGFR is calculated by the local labs using CKD-EPI. Units ml/min/1.73m2.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02336074

Contacts
Contact: Sarah Fidler, MD mrcctu.river@ucl.ac.uk
Contact: Sarah Pett, MD mrcctu.river@ucl.ac.uk

Locations
United Kingdom
Brighton and Sussex University Hospitals NHS Trust Recruiting
Brighton, United Kingdom
Contact: Amanda Clarke         
Central and North West London NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Sarah Pett         
Chelsea and Westminster NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Mark Nelson         
Guy's and St Thomas' NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Julie Fox         
Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom
Contact: Sarah Fidler         
Royal Free Hospital NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Margaret Johnson         
Sponsors and Collaborators
Imperial College London
Medical Research Council
University of Oxford
University of Cambridge
Chelsea and Westminster NHS Foundation Trust
Royal Free Hospital NHS Foundation Trust
Brighton and Sussex University Hospitals NHS Trust
Guy's and St Thomas' NHS Foundation Trust
Central and North West London NHS Foundation Trust
Investigators
Principal Investigator: Sarah Fidler, MD Imperial College London
  More Information

Additional Information:
Publications:

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02336074     History of Changes
Other Study ID Numbers: CCT-NAPN-24772  2014-001425-32 
Study First Received: October 23, 2014
Last Updated: October 10, 2016

Keywords provided by Imperial College London:
HIV
Vaccine
Cure
Early Intervention
Infection
Primary infection
Reservoir
Vorinostat
HDAC

Additional relevant MeSH terms:
Vaccines
Raltegravir Potassium
Vorinostat
Immunologic Factors
Physiological Effects of Drugs
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on February 20, 2017